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Histone Deacetylases As New Therapeutic Targets in Triple-Negative Breast Cancer

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Histone Deacetylases As New Therapeutic Targets in Triple-Negative Breast Cancer CANCER GENOMICS & PROTEOMICS 14 : 299-313 (2017) doi:10.21873/cgp.20041 Review Histone Deacetylases as New Therapeutic Targets in Triple- negative Breast Cancer: Progress and Promises NIKOLAOS GARMPIS 1* , CHRISTOS DAMASKOS 1,2* , ANNA GARMPI 3* , EMMANOUIL KALAMPOKAS 4, THEODOROS KALAMPOKAS 5, ELEFTHERIOS SPARTALIS 2, AFRODITE DASKALOPOULOU 2, SERENA VALSAMI 6, MICHAEL KONTOS 7, AFRODITI NONNI 8, KONSTANTINOS KONTZOGLOU 1, DESPINA PERREA 2, NIKOLAOS NIKITEAS 2 and DIMITRIOS DIMITROULIS 1 1Second Department of Propedeutic Surgery, Laiko General Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece; 2N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 3Internal Medicine Department, Laiko General Hospital, University of Athens Medical School, Athens, Greece; 4Gynaecological Oncology Department, University of Aberdeen, Aberdeen, U.K.; 5Assisted Conception Unit, Second Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 6Blood Transfusion Department, Aretaieion Hospital, Medical School, National and Kapodistrian Athens University, Athens, Greece; 7First Department of Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 8First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece Abstract. Triple-negative breast cancer (TNBC) lacks therapies. Given the fact that epigenetic processes control both expression of estrogen receptor (ER), progesterone receptor the initiation and progression of TNBC, there is an increasing (PR) and HER2 gene. It comprises approximately 15-20% of interest in the mechanisms, molecules and signaling pathways breast cancers (BCs). Unfortunately, TNBC’s treatment that participate at the epigenetic modulation of genes continues to be a clinical problem because of its relatively expressed in carcinogenesis. The acetylation of histone poor prognosis, its aggressiveness and the lack of targeted proteins provokes the transcription of genes involved in cell therapies, leaving chemotherapy as the mainstay of treatment. growth, and the expression of histone deacetylases (HDACs) It is essential to find new therapies against TNBC, in order to is frequently up-regulated in many malignancies. surpass the resistance and the invasiveness of already existing Unfortunately, in the field of BC, HDAC inhibitors have shown limited effect as single agents. Nevertheless, their use in combination with kinase inhibitors, autophagy inhibitors, This article is freely accessible online. ionizing radiation, or two HDAC inhibitors together is currently being evaluated. HDAC inhibitors such as *These Authors contributed equally to this study. suberoylanilidehydroxamic acid (SAHA), sodium butyrate, mocetinostat, panobinostat, entinostat, YCW1 and N-(2- Correspondence to: Nikolaos Garmpis, MD, Second Department of hydroxyphenyl)-2-propylpentanamide have shown promising Propedeutic Surgery, Laiko General Hospital, National and therapeutic outcomes against TNBC, especially when they are Kapodistrian University of Athens, Medical School, 17 Agiou used in combination with other anticancer agents. More Thoma Street, 11527, Athens, Greece. Tel: +30 6976291403, Fax: +30 2132061772, e-mail: [email protected] studies concerning HDAC inhibitors in breast carcinomas along with a more accurate understanding of the TNBC’s Key Words: Histone deacetylase, HDAC inhibitors, breast cancer, pathobiology are required for the possible identification of triple negative, epigenetics, review. new therapeutic strategies. 299 CANCER GENOMICS & PROTEOMICS 14 : 299-313 (2017) According to the World Health Organization, breast cancer Table I. Classification of breast cancers and their relation to breast (BC) is the most frequently diagnosed cancer and the second cancer cell lines. leading cause of cancer-related death, among women Classification Immuno-profile Cell line worldwide. Interestingly, according to the American Cancer Society about 12% of women in U.S.A. will develop BC Luminal A ER+, PR±, HER2- MCF-7, T47D during their lifetime (1-4). There is a variety of risk factors Luminal B ER+, PR±, HER2+ PR BT-474, ZR-75 that are associated with BC such as gender, age, ethnicity or HER2+ ER –, PR –, HER2+ MDA-MB-453 TNBC (Basal-like) ER –, PR –, HER2 – BT-20, MDA-MB-468 lifestyle, but it is now clear that the most dangerous factor for TNBC (Claudin-low) ER –, PR –, HER2 – BT549, Hs578T, the development of BC is heredity. In particular, in high-risk MDA-MB-231 families, there have been reported more than 1.000 mutations of breast cancer 1 ( BRCA1 ) and breast cancer 2 ( BRCA2 ) TNBC: Triple-negative breast cancer; ER: estrogen receptor; PR: genes (1). progesteron receptor. BC is a very heterogeneous disease given that its invasive process is associated with a variety of molecular alterations. These changes lead to different subtypes of the disease. The HDACs and their Μechanism of Αction current classification divides BC subtypes into Luminal A, Luminal B, HER2-positive and TNBC (5, 6). A better Today, several BC subtypes are treated with many different explanation of BC classification and the corresponding cell primary therapeutic protocols, but none of them uses lines are presented in Table I (7, 8). epigenetic drugs, despite the fact that the interest for First of all, Luminal A and B represent from 65% to 80% of epigenetics in BC tumorgenesis is increasing (12, 13). total BC disease. More specifically they account 50-60% and Gene regulation is affected by nucleosome packaging. 15-20% respectively (9). These subtypes are generally Nucleosome is the organizing DNA structure that is consisted correlated to a good prognosis. They are known to express the of about a 200 bp DNA coiled around an octameric core, estrogen receptor (ER-positive) that participates in cell consisted of histone proteins (14). proliferation, viability, and invasion of BC cells. We should N-terminal tails of histones extend outward from the mention that patients with luminal B tumors frequently present nucleosomal core and are modified by the covalent addition a worse prognosis than Luminal A patients. This could be of groups to the side chains of certain amino acids. These explained as in Luminal B tumors HER2 gene, which is modifications, including methylation, acetylation, associated with potent proliferation, can be amplified (10). The phosphorylation and the reverse processes, can change the substantial difference though, between Luminal A and B secondary DNA structure. As a result, gene promoter regions patients is the cell proliferation rate which is higher in the latter. become accessible or inaccessible to transcription factors (15). Secondly, there is the subtype of HER2-positive patients Histone acetyltransferases (HATs) catalyze the reversible who amplify the oncogene HER2 . These tumors are ER process of lysine acetylation at the ε- amino group of negative, so they are different from Luminal B cancers. proteinogenic lysine residues. Histone acetylation neutralizes Unfortunately, hormonotherapy is inefficient against HER2- the positive charge of lysine residues, therefore is correlated positive tumors. During the last 20 years the development to chromatin relaxation and active gene transcription (17). On of novel drugs targeting HER2 ( e.g. trastuzumab, lapatinib, the other hand, functional antagonists of HATs, histone pertuzumab) has enhanced the clinical outcomes (1). deacetylases (HDACs) remove the acetyl groups (16), thus Moreover, another severe subtype of BC is triple negative leading to compressed chromatin structure (heterochromatin), breast cancer (TNBC). It is associated with poor prognosis. and subsequently suppressing gene transcription (18) (Figure TNBC does not express either estrogen, or progesterone 1). Except for the direct effect of acetylation on chromatin receptors, or HER2 gene. These tumors can be further structure, gene regulation through acetylation is based on classified in several subtypes. The first subgroup is basal-like, synergistic actions. The specific acetylation patterns on histone where tumors express some characteristics of breast tails recruit further chromatin modulators that form co- myoepithelial cells. Basal-like tumors are highly proliferative repressor or co-activator complexes. and are associated with very poor prognosis. Another Several human HDACs have been identified; recently subgroup is claudin-low, which presents epithelial to HDACs have been classified into four classes in accordance mesenchymal transition (EMT) and stem cell-like or/and to functional criteria and homology to yeast proteins (19). In tumor initiating cell features (11). This subtype is also general, HDACs can be divided into Zn 2+ -dependent classes associated with poor prognosis. (class I, II and IV) and NAD-dependent classes (class III). Neoadjuvant anthracycline/taxane-based chemotherapies Class I is consisted of HDACs 1, 2, 3 and 8. Class II can be (e.g. , docetaxel, doxorubicin, cyclophosphamide) have been divided further into class IIa (HDAC4, 5, 7, and 9) and class tested in TNBC patients with poor prognosis (5). IIb (HDAC6 and 10). Class III members, or sirtuins as they 300 Garmpis et al : Histone Deacetylase Inhibitors in Triple Negative Breast Cancer (Review) Figure 1. Therapeutic strategy targeting histone deacetylases
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